The unique properties of silk proteins (SPs), particularly silk sericin (SS) and silk fibroin (SF), have attracted attention in the design of scaffolds for tissue engineering over the past decades. Since SF has good mechanical properties, while SS displays bioactivity, scaffolds combining both proteins should exhibit complementary properties enhancing the potential of these materials. Unfortunately, SS-SF composites can generate chronic immune responses and their immunogenic element is not completely clear. The potential of SS-SF composites in tissue engineering, elements which may contribute to their immunogenicity, and alternatives for their preparation and design, to modulate the immune response and take advantage of their useful properties, are discussed in this review. It is known that SS can enhance beta-sheet formation in SF, which may act as hydrophobic regions with a strong affinity for adsorption proteins inducing the chronic recruitment of inflammatory cells. Therefore, tailoring the exposure of hydrophobic regions at the scaffold surface should represent a viable strategy to modulate the immune response. This can be achieved by coating SS-SF composites with SS or other hydrophilic polymers, to take advantage of their antibiofouling properties. Research is still needed to realize the full potential of these composites for tissue engineering.